Betahistine, or a pharmaceutically acceptable salt thereof, and a monoamine oxidase inhibitor, for use in the treatment or prevention of one or more symptoms of vertigo in a subject

ABSTRACT

A first aspect of the invention relates to betahistine, or a pharmaceutically acceptable salt thereof, and a monoamine oxidase inhibitor, for use in the treatment or prevention of one or more symptoms of vertigo in a subject.A second aspect of the invention relates to a method of treating or preventing one or more symptoms of vertigo in a subject, said method comprising administering to the subject (i) betahistine, or a pharmaceutically acceptable salt thereof, and (ii) a monoamine oxidase inhibitor.

FIELD OF THE INVENTION

The present invention relates to combination therapy for the treatmentor prevention of one or more symptoms of vertigo.

BACKGROUND TO THE INVENTION

Vertigo is a commonly experienced symptom in which individualsexperience a false sensation of movement. Vertigo is a specific subtypeof dizziness thought to originate in the inner ear labyrinth or itsneural connections. Dizziness is a term that is commonly used bypatients to describe various sensations of light headedness, imbalance,illusory feelings of movement or disorientation. There are three typesof vertigo: peripheral, central and functional, depending on the cause.

Vertigo is defined by the Bárány Society (The International BalanceDisorders Association) as “the sensation of self-motion when noself-motion is occurring or the sensation of distorted self-motionduring an otherwise normal head movement” [46]. It may be a sensation ofrotation (spinning vertigo), or may be a different sensation of selfmotion (non-spinning vertigo). Peripheral vertigo is commonly caused byproblems with the inner ear and can in this context be referred to asvestibular vertigo.

The symptoms of vertigo are variable. In some cases symptoms may bemild, whilst in others there may be a single short-lived episode.Frequently, however, symptoms become prolonged, or individuals becomeprone to recurrent attacks. Importantly, vertigo increases the risk offalls, which is a major public health problem in the elderly. Vertigo isa subjective experience and its measurement is dependent on the accountof the individual experiencing it.

Peripheral vertigo has many causes including vestibular disorders suchas Menière's disease, vestibular neuritis and benign paroxysmalpositional vertigo, each of which can be diagnosed by standardizedcriteria.

Menière's disease is characterised by recurrent attacks of vertigo,fluctuating sensorineural hearing loss, aural fullness and tinnitus [1].Its histopathological hallmark is endolymphatic hydrops [2,3]. Lifetimeprevalence of the disease in the United States is reported as 190 per100 000 people, with a ratio of 1.89 women to every man [4,5]. Annualincidence of the disease in the USA was 15.3 per 100 000 people (ageadjusted rate) [6]. The peak age of onset is during the fifth and sixthdecade [7]. For patients with Menière's disease, unpredictable vertigoattacks are the most important and unpleasant symptom.

Many therapeutic approaches to Menière's disease have been studied.These include a low salt diet and diuretics [8], oral and intratympanicsteroid application [9,10] or minimal invasive interventions (such asinsertion of a ventilation tube into the tympanic membrane [11,12],endolymphatic sac surgery [13], or pulsed low pressure delivery (usingMeniett devices)) [14-17]. For patients who do not respond to thesetreatments, more aggressive procedures can be considered, such asintratympanic application of gentamycin [18,19], plugging of thesemicircular canal, labyrinthectomy, or neurectomy [20-23]. However,these interventions are irreversible and could damage the cochlear andvestibular organ. Furthermore, a recent review showed there was noevidence of any benefit in a surgical approach [24,25].

Betahistine is a licensed drug for Menière's disease-like symptomcomplexes, which contains the active ingredient betahistinedihydrochloride (maximum daily dose 48 mg) or betahistine dimesylate(maximum daily dose 36 mg). Betahistine is a strong H3 antagonist and aweak H1 agonist [26] with three sites of action. Firstly, it increasesdose-dependent cochlear blood flow [27], mainly via the H3 receptor asan inverse agonist [28]. Because betahistine has a strong first passeffect and is metabolised in the liver into three metabolites, not onlybetahistine but also its major metabolite aminoethylpyridine increasescochlear blood flow [29]. Secondly, betahistine increases histamineturnover in the central nervous and vestibular system, also mainly viathe H3 receptor. Thirdly, it decreases vestibular input in theperipheral vestibular system, with possible involvement with the H3 andH4 receptors.

How betahistine might have an effect in the prophylactic treatment ofMenière's disease is so far unknown. It could lead to an improvement oflabyrinthine microcirculation, thereby rebalancing the production andresorption of endolymph. The drug was first registered in Europe in the1970s and has been administered to more than 100 million patients sofar. In Germany, UK and most other European countries, betahistine isthe first line treatment for Menière's disease in clinical practice,before consideration of endolymphatic sac surgery or ablative gentamicintreatment [30]. The drug is inexpensive and well tolerated, and is oneof the most frequently prescribed drugs for Menière's disease in Europe[31,32].

Despite its widespread use in Europe, betahistine is not approved by theUS Food and Drug Administration, and observational studies or lowquality randomised controlled trials of low and moderate betahistinedoses have produced contradictory results on treatment efficacy. Severalclinical studies assessing the effect of betahistine on the vestibularsystem and, to a lesser degree, audiological symptoms suggested that thedrug improved these symptoms [33, 34]. However, according to a Cochranesystematic review of betahistine for Menière's disease or syndrome,there is insufficient evidence to indicate whether betahistine has anyeffect in currently approved dosages [33]. A more recent Cochrane reviewevaluated the effect of betathistine on the symptoms of vertigo [45].Whilst there may be a positive effect in terms of reduction in vertigosymptoms, there was significant variability in the results and thequality of data was adjudged to be low. Moreover, there was insufficientinformation about the effect of betahistine on objective tests of innerear balance organ function, and no information on the effect ofbetahistine on overall quality of life or falls. Until recently,randomised controlled trials that meet high quality standards werelacking, either due to inadequate diagnostic criteria or methods [35],or because the effect of betahistine treatment on vertigo wasinadequately assessed.

The dose of betahistine in these earlier studies varied between 16 and72 mg per day, which could explain the differences in symptom reliefobserved. Even higher doses of up to 480 mg per day have shown benefitfor severe cases in a small case series, suggesting a possible effect ofhigh dose regimens in the treatment of Menière's disease [37]. The drugseems to retain a good tolerability profile [33,45]. On the basis ofmany years' clinical experience, the dose was successively increased to48 mg three times a day, pointing towards the role of long termtreatment (up to 12 months). This dose increase was supported by anopen, uncontrolled, non-masked study without a placebo arm that compareda high dose regimen of 48 mg three times daily with the recommendedstandard dose of 16 or 24 mg three times daily [36]. Thisnon-interventional study showed that the higher dose was superior to thelower dose, and that the treatment effect of betahistine on theincidence of attacks of vertigo became more prominent over time.

More recently, a multicentre, double blind, randomised, placebocontrolled, phase III superiority trial was undertaken to assess thelong term prophylactic effects of betahistine dihydrochloride in twodifferent doses and placebo [39]. The doses and placebo wereadministered continuously for nine months, and effects observed on thefrequency, duration, and severity of acute attacks caused by Menière'sdisease, vertigo related impairment of quality of life, and vestibularand audiological function. The trial also aimed to ascertain the speedof effect—that is, whether the two active doses can be distinguishedfrom each other or from placebo by how quickly reduction in attackfrequency is achieved [38]. The results of the study indicated there wasno difference between the three treatment groups (placebo, low dose andhigh dose betahistine), i.e. long term prophylactic treatment withbetahistine dihydrochloride (at daily doses 2×24 mg or 3×48 mg) does notchange the time course of vertigo episodes related to Menière's diseasecompared with placebo. Placebo intervention as well as betahistinetreatment showed the same reduction of attack rates over the study'snine month treatment period.

In the light of the shortcomings of these studies, there is still anunmet need for new therapeutic treatments for the symptoms of vertigo,including those associated with Menière's disease. Indeed, this wasconfirmed in a recent Editorial article in the British Medical Journal(2016), where it was noted that the use of betahistine in treatingMenière's disease is ineffective, and that patients urgently need betteralternatives [40].

The present invention seeks to address this need by providing a newtherapeutic approach which comprises administering betahistine incombination with a second active agent, namely, a monoamine oxidaseinhibitor, for example, selegiline.

STATEMENT OF INVENTION

In a broad aspect, the present invention relates to a combinationcomprising betahistine, or a pharmaceutically acceptable salt thereof,and a monoamine oxidase inhibitor, and therapeutic uses thereof.Preferred embodiments are set out below and apply to all aspects as setout herein.

In a first aspect, the invention relates to betahistine, or apharmaceutically acceptable salt thereof, and a monoamine oxidaseinhibitor, for use in the treatment or prevention of one or moresymptoms of vertigo in a subject.

Advantageously, the applicants have shown that administeringbetahistine, or a pharmaceutically acceptable salt thereof, incombination with a monoamine oxidase inhibitor such as selegilinesurprisingly leads to an improved clinical outcome compared to patientsreceiving betahistine alone, for example, in terms of the number ofvertigo attacks experienced. Selegiline is a monoamine oxidase (MAO)inhibitor approved for the treatment of Parkinson's disease, alone or incombination with levodopa. To date, selegiline has not been disclosed asbeing therapeutically effective in the treatment of Menière's disease orother peripheral vestibular diseases, either alone or in combinationwith any other active agent.

The presently claimed combination treatment is unexpected given thatprevious clinical studies on betahistine monotherapy have beeninconclusive, and more recent reports have suggested that neither lowdoses nor high doses of betahistine are in fact clinically effective[39,40]. The administration of betahistine in combination with amonoamine oxidase inhibitor such as selegiline is able to achievetherapeutic efficacy with substantially lower doses of betahistine thanreported for betahistine monotherapy. This is reflected by a dramaticreduction in the number of betahistine tablets required per day. By wayof illustration, treatment with betahistine alone may require anythingfrom 40 to 80 tablets each day (24 mg per tablet), and even then, maystill not achieve a satisfactory therapeutic outcome for the patient. Incontrast, when betahistine is administered in combination withselegiline, the number of betahistine tablets can be drasticallyreduced, for example, to as few as 3 to 12 tablets per day, or even 3 to6 tablets per day.

A second aspect of the invention provides a combination comprising (i)betahistine, or a pharmaceutically acceptable salt thereof, and (ii) amonoamine oxidase inhibitor, for use in treating or preventing one ormore symptoms of vertigo in a subject.

A third aspect of the invention relates to the use of (i) betahistine,or a pharmaceutically acceptable salt thereof, and (ii) a monoamineoxidase inhibitor, in the preparation of a medicament for the treatmentor prevention of one or more symptoms of vertigo.

A fourth aspect of the invention relates to the use of a monoamineoxidase inhibitor, in the preparation of a medicament for the treatmentor prevention of one or more symptoms of vertigo, wherein saidmedicament is for use in combination therapy with betahistine, or apharmaceutically acceptable salt thereof.

A fifth aspect of the invention relates to the use of betahistine, or apharmaceutically acceptable salt thereof, in the preparation of amedicament for the treatment or prevention of one or more symptoms ofvertigo, wherein said medicament is for use in combination therapy witha monoamine oxidase inhibitor.

A sixth aspect of the invention relates to the use of betahistine, or apharmaceutically acceptable salt thereof, in the preparation of amedicament for the treatment or prevention of one or more symptoms ofvertigo, wherein said treatment comprises administering to a subjectsimultaneously, sequentially or separately a monoamine oxidaseinhibitor, and betahistine, or a pharmaceutically acceptable saltthereof.

A seventh aspect of the invention relates to the use of a monoamineoxidase inhibitor, in the preparation of a medicament for the treatmentor prevention of one or more symptoms of vertigo, wherein said treatmentcomprises administering to a subject simultaneously, sequentially orseparately betahistine, or a pharmaceutically acceptable salt thereof,and a monoamine oxidase inhibitor.

An eighth aspect relates to betahistine, or a pharmaceuticallyacceptable salt thereof, and a monoamine oxidase inhibitor, as acombined preparation for simultaneous, sequential or separate use intreating or preventing one or more symptoms of vertigo.

A ninth aspect of the invention relates to a method of treating orpreventing one or more symptoms of vertigo in a subject, said methodcomprising administering to the subject (i) betahistine, or apharmaceutically acceptable salt thereof, and (ii) a monoamine oxidaseinhibitor.

DETAILED DESCRIPTION

As mentioned above, one aspect of the invention relates to betahistine,or a pharmaceutically acceptable salt thereof, and a monoamine oxidaseinhibitor, for use in combination therapy in the treatment or preventionof one or more symptoms of vertigo in a subject.

Administering the betahistine in combination with a monoamine oxidaseinhibitor such as selegiline surprisingly renders the betahistinetherapeutically useful in the treatment of peripheral vertigo, forexample, in treating Menière's disease.

Preferably, the subject is a mammal, more preferably, a human.

As used herein, “treatment or prevention” includes preventing oralleviating one or more symptoms of vertigo. Symptoms of vertigoinclude, but are not limited to, false sensation of movement, dizziness,light headedness, imbalance and illusory feelings of movement ordisorientation.

In one preferred embodiment, the invention relates to treating one ormore symptoms of vertigo in a subject.

In another preferred embodiment, the invention relates to preventing oneor more symptoms of vertigo in a subject.

In one preferred embodiment, the combination therapy reduces thefrequency and/or severity of one or more symptoms of vertigo. In onehighly preferred embodiment, the combination therapy reduces thefrequency and/or severity of vertigo attacks experienced by the subject.

In one preferred embodiment, the vertigo is peripheral vertigo.Peripheral vertigo is commonly caused by problems with the inner ear,which controls balance.

In another preferred embodiment, the vertigo is central vertigo. Centralvertigo is vertigo due to a disease originating from the central nervoussystem (CNS). Individuals with vertigo experience hallucinations ofmotion of their surroundings. Central vertigo may be caused byhemorrhagic or ischemic insults to the cerebellum, the vestibularnuclei, and their connections within the brain stem. Other causesinclude CNS tumors, infection, trauma, and multiple sclerosis.

In one preferred embodiment, the peripheral vertigo is acute vertigo.Preferably, the treatment reduces the symptoms of acute central vertigoand improves central compensation.

The effect of drug combinations is inherently unpredictable and there isoften a propensity for one drug to partially or completely inhibit theeffects of the other. The present invention is based on the surprisingobservation that administering behistine, or a pharmaceuticallyacceptable salt thereof, in combination, either simultaneously,separately or sequentially, with selegiline, or a pharmaceuticallyacceptable salt thereof, does not lead to any adverse interactionbetween the two agents. The unexpected absence of any such antagonisticinteraction is critical for clinical applications.

In a preferred embodiment, the combination of betahistine, or apharmaceutically acceptable salt thereof, and monoamine oxidaseinhibitor produces an enhanced effect as compared to either drugadministered alone. The surprising nature of this observation is incontrast to that expected on the basis of the prior art, and inparticular, the observed lack of efficacy and contradictory clinicalreports in relation to betahistine monotherapy. Without wishing to bebound by theory, it is believed that selegiline, which is an MAOinhibitor, reduces the first pass effect and leads to an increase in theblood concentration of betahistine.

The preferred embodiments as set out below are applicable to all theabove-mentioned aspects of the invention.

In one preferred embodiment, the peripheral vertigo is caused by, orassociated with, Menière's disease. Thus, in one embodiment, thecombination is for use in treating Menière's disease.

Menière's disease is characterised by recurrent attacks of vertigo,fluctuating sensorineural hearing loss, aural fullness and tinnitus [1].The Bárány Society and international collaborating organisations haverecently published consensus clinical criteria for Menière's disease[49], taking forward the previously widely used American criteria [50].

One preferred embodiment of the invention relates to betahistine, or apharmaceutically acceptable salt thereof, and a monoamine oxidaseinhibitor, for use in the treatment of Menière's disease. Preferably,the treatment reduces or prevents the number of peripheral vertigoattacks in a subject suffering from Menière's disease.

Another preferred embodiment of the invention relates to betahistine, ora pharmaceutically acceptable salt thereof, and seleginine or apharmaceutically acceptable salt thereof, for use in the treatment ofMenière's disease.

As used herein, “treatment of Menière's disease” includes preventing oralleviating one or more symptoms of the disease, which symptoms includevertigo, fluctuating sensorineural hearing loss, aural fullness andtinnitus. In one preferred embodiment, the combination therapy reducesthe frequency and/or severity of one or more symptoms of the disease. Inone highly preferred embodiment, the combination therapy reduces thefrequency and/or severity of Menière's attacks experienced by thesubject.

In another preferred embodiment, peripheral vertigo is caused by, orassociated with, vestibular neuritis, also called vestibular neuronitisor nowadays acute unilateral peripheral vestibulopathy. One preferredembodiment of the invention thus relates to betahistine, or apharmaceutically acceptable salt thereof, and a monoamine oxidaseinhibitor, for use in the treatment of vestibular neuritis. Vestibularneuritis is characterized by an acute onset of severe spinning vertigo,postural imbalance, nausea and often vomiting. Clinical examinationreveals a peripheral vestibular spontaneous nystagmus and a pathologicalhead impulse test and Romberg test. It is assumed to be caused in mostpatients by the reactivation of an Herpes simplex virus type 1 infection[50].

Similar signs and symptoms can also be caused by a trauma to thevestibular nerve or labyrinth (concussion), by an ischemia of thelabyrinth or an inflammation of the ear by Herpes zoster virus orbacteria. The same symptoms can also occur in patients with brainstem orcerebellar infarction (“vestibular pseudoneuritis”).

In another preferred embodiment, the peripheral vertigo is caused by, orassociated with, benign paroxysmal positional vertigo (BPPV). Onepreferred embodiment of the invention thus relates to betahistine, or apharmaceutically acceptable salt thereof, and a monoamine oxidaseinhibitor, for use in the treatment of BPPV. Benign paroxysmalpositional vertigo develops when small crystals of calcium carbonatebreak free and find their way to the semicircular canal in the innerear. This causes the brain to receive confusing messages about thebody's position. Benign paroxysmal positional vertigo is diagnosedaccording to clinical criteria, as is vestibular neuritis [48].

In another preferred embodiment, the peripheral vertigo is caused by, orassociated with, labyrinthitus. One preferred embodiment of theinvention thus relates to betahistine, or a pharmaceutically acceptablesalt thereof, and a monoamine oxidase inhibitor, for use in thetreatment of labyrinthitus. Labyrinthitis is swelling and inflammationof the labyrinth, part of the inner ear that helps control balance.Labyrinthitis can occur after a viral infection or, more rarely, afteran infection caused by bacteria.

As used herein the phrase “preparation of a medicament” includes the useof the components of the invention directly as the medicament inaddition to their use in any stage of the preparation of such amedicament.

As used herein, the term “combination therapy” refers to therapy inwhich the betahistine, or pharmaceutically acceptable salt thereof, andthe monoamine oxidase inhibitor, are administered if not simultaneously,then sequentially within a timeframe, that they both are available toact therapeutically within the same time-frame.

The betahistine, or a pharmaceutically acceptable salt thereof, andmonoamine oxidase inhibitor, may be administered simultaneously, incombination, sequentially or separately (as part of a dosing regime).

As used herein, “simultaneously” is used to mean that the two agents areadministered concurrently, whereas the term “in combination” is used tomean they are administered, if not simultaneously, then “sequentially”within a timeframe that they both are available to act therapeuticallywithin the same time-frame. Thus, administration “sequentially” maypermit one agent to be administered within 5 minutes, 10 minutes or amatter of hours after the other provided the circulatory half-life ofthe first administered agent is such that they are both concurrentlypresent in therapeutically effective amounts. The time delay betweenadministration of the components will vary depending on the exact natureof the components, the interaction therebetween, and their respectivehalf-lives.

In contrast to “in combination” or “sequentially”, “separately” is usedherein to mean that the gap between administering one agent and theother is significant i.e. the first administered agent may no longer bepresent in the bloodstream in a therapeutically effective amount whenthe second agent is administered.

In one preferred embodiment of the invention, the betahistine isadministered sequentially or separately prior to the monoamine oxidaseinhibitor.

In another particularly preferred embodiment, the monoamine oxidaseinhibitor is administered sequentially or separately prior to thebetahistine.

In one preferred embodiment, the betahistine and monoamine oxidaseinhibitor are each administered in a therapeutically effective amountwith respect to the individual components; in other words, thebetahistine and monoamine oxidase inhibitor are administered in amountsthat would be therapeutically effective even if the components wereadministered other than in combination.

In another preferred embodiment, the betahistine and monoamine oxidaseinhibitor are each administered in a sub-therapeutic amount with respectto the individual components; in other words, the betahistine andmonoamine oxidase inhibitor are administered in amounts that would betherapeutically ineffective if the components were administered otherthan in combination.

In one preferred embodiment, the betahistine and monoamine oxidaseinhibitor interact in a synergistic manner. As used herein, the term“synergistic” means that betahistine and monoamine oxidase inhibitorproduce a greater effect when used in combination than would be expectedfrom adding the individual effects of the two components.Advantageously, a synergistic interaction may allow for lower doses ofeach component to be administered to a patient, thereby decreasingtoxicity, whilst producing and/or maintaining the same therapeuticeffect. Thus, in a particularly preferred embodiment, each component canbe administered in a sub-therapeutic amount.

In another preferred embodiment, the betahistine and monoamine oxidaseinhibitor produce a greater effect when used in combination than wouldbe expected based on the effect of betahistine alone. Advantageously,the interaction between the betahistine and monoamine oxidase inhibitorallows for lower doses of betahistine to be administered to a patient,thereby decreasing toxicity, whilst producing and/or maintaining thesame therapeutic effect.

Another aspect of the invention relates to a combination comprising (i)betahistine, or a pharmaceutically acceptable salt thereof, and (ii) amonoamine oxidase inhibitor, for use in treating or prevention one ormore symptoms of vertigo in a subject. As used herein, the term“combination” refers to the actives being in a single formulation, or inseparate formulations. Preferably, the actives are in separateformulations. Where the monoamine oxidase inhibitor (e.g. selegiline)and the betahistine or pharmaceutically acceptable salt thereof, areadministered in the same formulation, preferably the dosage of monoamineoxidase inhibitor is low enough such that the total daily dosage doesnot exceed 5 mg per day. For example, in one particularly preferredembodiment, the formulation may comprise 24 mg betahistine and 0.5 mg ofselegiline per unit dosage (or tablet).

Another aspect of the invention relates to the use of (i) betahistine,or a pharmaceutically acceptable salt thereof, and (ii) a monoamineoxidase inhibitor, in the preparation of a medicament for the treatmentor prevention of one or more symptoms of vertigo.

Another aspect of the invention relates to the use of a monoamineoxidase inhibitor, or a pharmaceutically acceptable salt thereof, in thepreparation of a medicament for the treatment or prevention of one ormore symptoms of vertigo, wherein said medicament is for use incombination therapy with betahistine, or a pharmaceutically acceptablesalt thereof.

Another aspect of the invention relates to the use of betahistine, or apharmaceutically acceptable salt thereof, in the preparation of amedicament for the treatment or prevention of one or more symptoms ofvertigo, wherein said medicament is for use in combination therapy witha monoamine oxidase inhibitor.

Another aspect of the invention relates to the use of betahistine, or apharmaceutically acceptable salt thereof, in the preparation of amedicament for the treatment or prevention of one or more symptoms ofvertigo, wherein said treatment comprises administering to a subjectsimultaneously, sequentially or separately a monoamine oxidaseinhibitor, and betahistine, or a pharmaceutically acceptable saltthereof.

Another aspect of the invention relates to the use of a monoamineoxidase inhibitor in the preparation of a medicament for the treatmentor prevention of one or more symptoms of vertigo, wherein said treatmentcomprises administering to a subject simultaneously, sequentially orseparately betahistine, or a pharmaceutically acceptable salt thereof,and a monoamine oxidase inhibitor.

Another aspect of the invention relates to betahistine, or apharmaceutically acceptable salt thereof, and a monoamine oxidaseinhibitor as a combined preparation for simultaneous, sequential orseparate use in treating or prevention of one or more symptoms ofvertigo.

Another aspect of the invention relates to a method of treating orpreventing one or more symptoms of vertigo in a subject, said methodcomprising administering to the subject (i) betahistine, or apharmaceutically acceptable salt thereof, and (ii) a monoamine oxidaseinhibitor.

Another preferred aspect of the invention relates to a method oftreating Menière's disease in a subject, said method comprisingadministering to the subject (i) betahistine, or a pharmaceuticallyacceptable salt thereof, and (ii) a monoamine oxidase inhibitor.

Another preferred embodiment of the invention relates to a method oftreating Menière's disease in a subject, said method comprisingadministering to a subject (i) betahistine, or a pharmaceuticallyacceptable salt thereof, and (ii) seleginine or a pharmaceuticallyacceptable salt thereof.

Betahistine

Betahistine is a histamine analogue known as2-[2-(methylamino)ethyl]pyridine and having the structure shown below:

Betahistine is prescribed for the treatment of Menière's disease. It istypically formulated as the dihydrochloride salt and is available underthe brand names Veserc, Serc, Hiserk, Betaserc and Vergo. Commonlysupplied as a tablet for oral administration, each tablet typicallycontains between 8-24 mg of betahistine dihydrochloride, with a totaldaily dosage for adults between 24-48 mg per day, preferably dividedinto three equal doses.

Studies in an animal model [41] suggest that betahistine acts as strongH3 receptor antagonist, leading to vasodilation of the anterior inferiorcerebellar artery and an increase in cochlear blood flow. It is thoughtthat this increase in cochlear blood flow leads to greater resorption ofendolymph into the subarachnoid space and a reduction in swelling of themembranous labyrinth [42], leading to a reduced frequency of attacks.

Whilst betahistine is approved for the treatment of Menière's disease inEurope, there is still insufficient evidence to demonstrate atherapeutically beneficial effect [43]. Accordingly, effectivetreatments for Menière's disease are still required.

Monoamine Oxidase Inhibitors

Monoamine oxidases (MAO) are a family of enzymes that catalyze theoxidative deamination of monoamines. They are found bound to the outermembrane of mitochondria in most cell types in the body and belong tothe protein family of flavin-containing amine oxidoreductases. In humansthere are two types of MAO: MAO-A and MAO-B. Both are found in neuronsand astroglia. MAO-A is also found in the liver, pulmonary vascularendothelium, gastrointestinal tract, and placenta. MAO-B is mostly foundin blood platelets.

Both MAOs are also vital to the inactivation of monoaminergicneurotransmitters, for which they display different specificities.Serotonin, melatonin, norepinephrine, and epinephrine are mainly brokendown by MAO-A, whereas phenethylamine and benzylamine are mainly brokendown by MAO-B. Both forms break down dopamine, tyramine, and tryptamineequally. In view of their role in the inactivation of neurotransmitters,MAO dysfunction is thought to be responsible for a number of psychiatricand neurological disorders. MAO-A inhibitors act as antidepressant andantianxiety agents, whereas MAO-B inhibitors are used alone or incombination to treat Alzheimer's and Parkinson's diseases.

Some MAO inhibitors inhibit both MAO-A and MAO-B equally, whereas othershave been developed to target one over the other. Non-selectiveMAO-A/MAO-B inhibitors include the hydrazines Isocarboxazid (Marplan),Nialamide (Niamid), Phenelzine (Nardil, Nardelzine), Hydracarbazine, andthe non-hydrazine Tranylcypromine (Parnate, Jatrosom). Other examples ofnon-selective MAO-A/MAO-B inhibitors include Benmoxin (Nerusil,Neuralex), Iproclozide (Sursum), Iproniazid (Marsilid, Iprozid, Ipronid,Rivivol, Propilniazida) (discontinued worldwide except for France),Mebanazine (Actomol), Octamoxin (Ximaol, Nimaol), Pheniprazine (Catron),Phenoxypropazine (Drazine), Pivalylbenzhydrazine (Tersavid), Safrazine(Safra) (discontinued worldwide except for Japan) and Caroxazone(Surodil, Timostenil).

In one highly preferred embodiment, the monamine oxidase inhibitor is aMAO-A inhibitor. Examples of MAO-A inhibitors include, but are notlimited to, Bifemelane (Alnert, Celeport; available in Japan),Moclobemide (Aurorix, Manerix), Pirlindole (Pirazidol; available inRussia), Toloxatone (Humoryl; available in France) and Minaprine(Cantor).

In another highly preferred embodiment, the monamine oxidase inhibitoris a MAO-B inhibitor. Examples of MAO-B inhibitors include, but are notlimited to, selegiline and rasagiline.

Standard laboratory assays can be used to determine whether a compoundis a MAO-A or MAO-B inhibitor (e.g. Monoamine Oxidase Assay Kitavailable from Sigma Aldrich, which is a fluorimetric assay; or CyprotexMonoamine Oxidase Assay Kit).

Selegiline

In one highly preferred embodiment, the monamine oxidase-B inhibitor isselegiline, or a pharmaceutically acceptable salt thereof. Morepreferably, the monamine oxidase-B inhibitor is selegilinehydrochloride.

Selegiline (also known as L-deprenyl), is a substituted phenethylamineknown as N-methyl-N-(2-propynyl)-2-methyl-1-phenylethyl-2-amine andhaving the structure shown below:

Selegiline is an irreversible MOA-B inhibitor prescribed for thetreatment of Parkinson's disease, often in combination with L-dopa [53,54]. Selegiline also inhibits MOA-A at certain doses. A transdermalpatch (brand name, Emsam) is used to treat depression. To date,selegiline has not been disclosed as being therapeutically useful in thetreatment of Menière's disease, either alone or in combination with anyother active agent.

Selegiline's ability to inhibit MOA-B has rendered it a useful agent inthe treatment of Parkinson's disease. When used alone, in the earlystages of Parkinson's disease, selegiline exerts a mild beneficialtherapeutic effect and delays the need for L-Dopa therapy. When used incombination with L-Dopa, selegiline potentiates the effects of L-Dopaand allows for a reduction in the required daily dosage, leading tofewer L-Dopa associated side effects. In addition to its MOA-Binhibitory activity, selegiline has recently been shown in vitro [44] todelay α-synuclein fibril formation by inhibiting initial nucleiformation and to a lesser extent, subsequent fibril elongation.

Betahistine Pretreatment

In one embodiment, the subject is treatment naive, i.e has not receivedprior treatment with betahistine. In another embodiment, the presentlyclaimed combination therapy is particularly effective in subjects thathave previously received betahistine monotherapy, for example, subjectswhere administering treatment with betahistine alone has provedtherapeutically ineffective, or where the subject requires extremelyhigh daily doses of the drug for it to have a therapeuticallysignificant effect.

In one preferred embodiment, the subject has been previously treated(pretreated) with betahistine, or a pharmaceutically acceptable saltthereof.

As used herein, a “therapeutically significant effect” refers to thesubject being free of attacks (e.g. vertigo symptoms associated withMenière's disease) for a specific period of time, for example, at leastthree months.

As used herein, “betahistine monotherapy” refers to treatment withbetahistine, or a pharmaceutically acceptable salt thereof, in theabsence of selegiline, or a pharmaceutically acceptable salt thereof.Preferably, the betahistine is administered in the absence of any otheractive agent.

As used herein, the term “pretreated” means that the subject hasreceived monotherapy with betahistine, or a pharmaceutically acceptablesalt thereof, for a period of time prior to commencement of combinationtherapy.

More preferably, the subject has received betahistine, or apharmaceutically acceptable salt thereof, for a period of at least 6months, more preferably, at least 12 months prior to commencement ofcombination therapy. During this pretreatment period, the subject'sresponse to monotherapy with betahistine can be evaluated, including theoptimal daily dose required to achieve a therapeutically significanteffect.

Betahistine monotherapy is approved in Europe for treatment of Menière'ssyndrome, the symptoms of which include vertigo, tinnitus, hearing lossand nausea. According to the Summary of Product Characteristics, themaximum dose is 48 mg per day. However, recent clinical studies haveindicated that this dose, and indeed higher doses (48 mg three times aday), are not effective in the treatment of Menière's disease [39,40].

In one preferred embodiment, the subject has been previously treatedwith betahistine monotherapy for a period of at least 12 months, but atherapeutically significant effect has not been achieved, i.e. thesubject has not been free of attacks of Menière's disease symptoms forat least three months.

In one preferred embodiment, the subject has received betahistine, or apharmaceutically acceptable salt thereof, for a period of at least 12months prior to the start of the combination therapy, in an amount ofgreater than 48 mg per day.

In another preferred embodiment, the subject has received betahistine,or a pharmaceutically acceptable salt thereof, for a period of at least12 months prior to the start of the combination therapy, in an amount ofgreater than 120 mg per day.

In another preferred embodiment, the subject has received betahistine,or a pharmaceutically acceptable salt thereof, for a period of at least12 months prior to the start of the combination therapy, in an amount ofgreater than 240 mg per day.

In another preferred embodiment, the subject has received betahistine,or a pharmaceutically acceptable salt thereof, for a period of at least12 months prior to the start of the combination therapy, in an amount ofgreater than 480 mg per day.

In some instances, studies by the Applicant have indicated that subjectsrequire at least 20 tablets per day (24 mg betahistine per tablet), insome cases even more (for example, from 40 to 60 and even 80×24 mgtablets per day), in order to observe a therapeutically significanteffect with betahistine monotherapy. These subjects are particularlysuitable for subsequent combination therapy with betahistine and amonoamine oxidase inhibitor such as selegiline. Using the presentlyclaimed combination treatment, the daily dosage of betahistine can besignificantly reduced, for example, to as few as 18×24 mg tablets perday, or 12×24 mg tablets per day, or even as few as 3×24 mg tablets perday.

Salts

The agents of the present invention can be present as salts, inparticular pharmaceutically acceptable salts or esters.

Pharmaceutically acceptable salts of the agents of the invention includesuitable acid addition or base salts thereof. A review of suitablepharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19(1977). Salts are formed, for example with strong inorganic acids suchas mineral acids, e.g. sulphuric acid, phosphoric acid or hydrohalicacids; with strong organic carboxylic acids, such as alkanecarboxylicacids of 1 to 4 carbon atoms which are unsubstituted or substituted(e.g., by halogen), such as acetic acid; with saturated or unsaturateddicarboxylic acids, for example oxalic, malonic, succinic, maleic,fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, forexample ascorbic, glycolic, lactic, malic, tartaric or citric acid; withaminoacids, for example aspartic or glutamic acid; with benzoic acid; orwith organic sulfonic acids, such as (C₁-C₄)-alkyl- or aryl-sulfonicacids which are unsubstituted or substituted (for example, by a halogen)such as methane- or p-toluene sulfonic acid.

In one preferred embodiment, the betahistine is in the form ofbetahistine dihydrochloride.

In another preferred embodiment, the betahistine is in the form ofbetahistine mesylate.

In one preferred embodiment, the selegiline is in the form of selegilinehydrochloride.

Pharmaceutical Carriers, Excipients or Diluents

The actives of the present combination are typically administered inadmixture with a pharmaceutical carrier, excipient or diluent,particularly for human therapy. Examples of such suitable excipients forthe various different forms of pharmaceutical compositions describedherein may be found in the “Handbook of Pharmaceutical Excipients,2^(nd) Edition, (1994), Edited by A Wade and PJ Weller. Acceptablecarriers or diluents for therapeutic use are well known in thepharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol and the like. Examplesof suitable diluents include ethanol, glycerol and water.

The choice of pharmaceutical carrier, excipient or diluent can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as, or in addition to, the carrier, excipient or diluent anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s),solubilising agent(s). Examples of suitable binders include starch,gelatin, natural sugars such as glucose, anhydrous lactose, free-flowlactose, beta-lactose, corn sweeteners, natural and synthetic gums, suchas acacia, tragacanth or sodium alginate, carboxymethyl cellulose andpolyethylene glycol. Examples of suitable lubricants include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. Preservatives, stabilizers, dyesand even flavoring agents may be provided in the pharmaceuticalcomposition. Examples of preservatives include sodium benzoate, sorbicacid and esters of p-hydroxybenzoic acid. Antioxidants and suspendingagents may be also used.

Enantiomers/Tautomers

The invention also includes where appropriate all enantiomers andtautomers of the agents. The man skilled in the art will recognisecompounds that possess an optical properties (one or more chiral carbonatoms) or tautomeric characteristics. The corresponding enantiomersand/or tautomers may be isolated/prepared by methods known in the art.

Stereo and Geometric Isomers

Some of the agents of the invention may exist as stereoisomers and/orgeometric isomers—e.g. they may possess one or more asymmetric and/orgeometric centres and so may exist in two or more stereoisomeric and/orgeometric forms. The present invention contemplates the use of all theindividual stereoisomers and geometric isomers of those inhibitoragents, and mixtures thereof. The terms used in the claims encompassthese forms, provided said forms retain the appropriate functionalactivity (though not necessarily to the same degree).

The present invention also includes all suitable isotopic variations ofthe agent or pharmaceutically acceptable salts thereof. An isotopicvariation of an agent of the present invention or a pharmaceuticallyacceptable salt thereof is defined as one in which at least one atom isreplaced by an atom having the same atomic number but an atomic massdifferent from the atomic mass usually found in nature. Examples ofisotopes that can be incorporated into the agent and pharmaceuticallyacceptable salts thereof include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certainisotopic variations of the agent and pharmaceutically acceptable saltsthereof, for example, those in which a radioactive isotope such as ³H or¹⁴C is incorporated, are useful in drug and/or substrate tissuedistribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with isotopes such as deuterium,i.e., ²H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements and hence may be preferred in somecircumstances. Isotopic variations of the agent of the present inventionand pharmaceutically acceptable salts thereof of this invention cangenerally be prepared by conventional procedures using appropriateisotopic variations of suitable reagents.

Solvates

The present invention also includes solvate forms of the agents of thepresent invention. The terms used in the claims encompass these forms.

Polymorphs

The invention furthermore relates to agents of the present invention intheir various crystalline forms, polymorphic forms and (an)hydrousforms. It is well established within the pharmaceutical industry thatchemical compounds may be isolated in any of such forms by slightlyvarying the method of purification and or isolation form the solventsused in the synthetic preparation of such compounds.

Prodrugs

The invention further includes agents of the present invention inprodrug form. Such prodrugs are generally compounds wherein one or moreappropriate groups have been modified such that the modification may bereversed upon administration to a human or mammalian subject. Suchreversion is usually performed by an enzyme naturally present in suchsubject, though it is possible for a second agent to be administeredtogether with such a prodrug in order to perform the reversion in vivo.Examples of such modifications include ester (for example, any of thosedescribed above), wherein the reversion may be carried out be anesterase etc. Other such systems will be well known to those skilled inthe art.

Administration

The pharmaceutical compositions of the present invention may be adaptedfor oral, rectal, vaginal, parenteral, intramuscular, intraperitoneal,intraarterial, intrathecal, intrabronchial, subcutaneous, intradermal,intravenous, nasal, buccal or sublingual routes of administration.

Preferably, the monoamine oxidase inhibitor (e.g. selegiline), orpharmaceutically acceptable salt thereof, is formulated for oraladministration.

Preferably, the betahistine, or pharmaceutically acceptable saltthereof, is formulated for oral administration.

For oral administration, particular use is made of compressed tablets,pills, tablets, gellules, drops, and capsules. Preferably, thesecompositions contain from 1 to 2000 mg and more preferably from 50-1000mg, of active ingredient per dose.

Other forms of administration comprise solutions or emulsions which maybe injected intravenously, intraarterially, intrathecally,subcutaneously, intradermally, intraperitoneally or intramuscularly, andwhich are prepared from sterile or sterilisable solutions. Thepharmaceutical compositions of the present invention may also be in formof suppositories, pessaries, suspensions, emulsions, lotions, ointments,creams, gels, sprays, solutions or dusting powders.

An alternative means of transdermal administration is by use of a skinpatch. For example, the active ingredient can be incorporated into acream consisting of an aqueous emulsion of polyethylene glycols orliquid paraffin. The active ingredient can also be incorporated, at aconcentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilisers and preservatives as may be required.

Injectable forms may contain between 10-1000 mg, preferably between10-500 mg, of active ingredient per dose.

Compositions may be formulated in unit dosage form, i.e., in the form ofdiscrete portions containing a unit dose, or a multiple or sub-unit of aunit dose.

In one preferred embodiment, the betahistine, or pharmaceuticallyacceptable salt thereof, is administered orally, preferably in tabletform.

In one preferred embodiment, the monoamine oxidase inhibitor (e.g.selegiline, or pharmaceutically acceptable salt thereof), isadministered orally, preferably in tablet form.

Dosage

A person of ordinary skill in the art can easily determine anappropriate dose of one of the instant compositions to administer to asubject without undue experimentation. Typically, a physician willdetermine the actual dosage which will be most suitable for anindividual patient and it will depend on a variety of factors includingthe activity of the specific compound employed, the metabolic stabilityand length of action of that compound, the age, body weight, generalhealth, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and theindividual undergoing therapy. The dosages disclosed herein areexemplary of the average case. There can of course be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

Dosages and frequency of application are typically adapted to thegeneral medical condition of the patient and to the severity of theadverse effects caused, in particular to those caused to thehematopoietic, hepatic and to the renal system. The total daily dose canbe administered as a single dose or divided into separate dosagesadministered two, three or four time a day.

In one preferred embodiment, the betahistine or pharmaceuticallyacceptable salt thereof is administered in an amount of from about 50 toabout 900 mg per day, preferably from about 50 to about 500 mg per day,even more preferably, from about 50 to about 300 mg per day, morepreferably from about 100 to about 300, or about 100 to about 200 mg perday.

In a more preferred embodiment, the betahistine or pharmaceuticallyacceptable salt thereof is administered in an amount of from about 70 toabout 290 mg per day. In one embodiment, the total daily dose is fromabout 72 to about 864 mg (e.g. from 3 to 36×24 mg tablets). Preferably,the total daily dose is from about 72 to about 432 mg (e.g. from 3 to18×24 mg tablets). More preferably, the total daily dose is from about72 to about 288 mg (e.g. from 3 to 12×24 mg tablets). In anotherembodiment, the total daily dose is from about 72 to about 144 mg (e.g.from 3 to 6×24 mg tablets), or from about 72 to about 216 mg (e.g. from3 to 9×24 mg tablets), or or from about 72 to about 360 mg (e.g. from 3to 15×24 mg tablets), or from about 72 to about 576 mg (e.g. from 3 to24×24 mg tablets), or from about 72 to about 720 mg (e.g. from 3 to30×24 mg tablets). In another preferred embodiment, the total daily doseis no greater than 432 mg. In another preferred embodiment, the totaldaily dose is no greater than 288 mg per day.

In one preferred embodiment, the betahistine or pharmaceuticallyacceptable salt thereof is administered once, twice or three times aday. More preferably, the betahistine or pharmaceutically acceptablesalt thereof is administered three times a day, for example, morning,lunchtime and night time.

In one preferred embodiment, the betahistine or pharmaceuticallyacceptable salt thereof is administered in unit dosage form.

In one preferred embodiment, the unit dosage comprises a 24 mg tablet ofbetahistine dihydrochloride, wherein from 3 to 18 tablets areadministered per day, or 3 to 12, or 3 to 10, or 3 to 8, or 3 to 6tablets per day.

The skilled person would understand that other unit dosages could alsobe used with the number of tablets adjusted accordingly to giveequivalent daily dosages to those described herein.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein from 4 to 18 tablets areadministered per day, or 5 to 15, or 6 to 12, or 6 to 8, or 8 to 10tablets per day.

In one preferred embodiment, the unit dosage comprises a 24 mg tablet ofbetahistine dihydrochloride, wherein from 3 to 36 tablets areadministered per day, more preferably from 3 to 30, or from 3 to 24tablets per day.

In one particularly preferred embodiment, the unit dosage comprises a 24mg tablet of betahistine dihydrochloride, wherein from 3 to 12 tabletsare administered per day.

In one preferred embodiment, the unit dosage comprises a 24 mg tablet ofbetahistine dihydrochloride, wherein 3 tablets are administered per day.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein 6 tablets areadministered per day.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein 9 tablets areadministered per day.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein 12 tablets areadministered per day.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein 15 tablets areadministered per day.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein 18 tablets areadministered per day.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein 24 tablets areadministered per day.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein 30 tablets areadministered per day.

In another preferred embodiment, the unit dosage comprises a 24 mgtablet of betahistine dihydrochloride, wherein 36 tablets areadministered per day.

In one particularly preferred embodiment, the betahistine orpharmaceutically acceptable salt thereof is administered in a totaldaily dosage of no greater than 36×24 mg tablets, i.e. no greater than864 mg per day.

In one particularly preferred embodiment, the betahistine orpharmaceutically acceptable salt thereof is administered in a totaldaily dosage of no greater than 18×24 mg tablets, i.e. no greater than432 mg per day.

In one particularly preferred embodiment, the betahistine orpharmaceutically acceptable salt thereof is administered in a totaldaily dosage of no greater than 12×24 mg tablets, i.e. no greater than288 mg per day.

In one particularly preferred embodiment, the betahistine orpharmaceutically acceptable salt thereof is administered in a totaldaily dosage of no greater than 15×24 mg tablets, i.e. no greater than360 mg per day.

In one particularly preferred embodiment, the betahistine orpharmaceutically acceptable salt thereof is administered in a totaldaily dosage of no greater than 24×24 mg tablets, i.e. no greater than576 mg per day.

In one particularly preferred embodiment, the betahistine orpharmaceutically acceptable salt thereof is administered in a totaldaily dosage of no greater than 30×24 mg tablets, i.e. no greater than720 mg per day.

In one preferred embodiment, the monoamine oxidase inhibitor orpharmaceutically acceptable salt thereof is administered in an amount offrom about 1 to about 15 mg per day, more preferably, about 1.25 toabout 10 mg/day.

In one preferred embodiment, the monoamine oxidase inhibitor orpharmaceutically acceptable salt thereof is administered in an amount ofabout 5 to about 10 mg per day. In one highly preferred embodiment, theselegiline or pharmaceutically acceptable salt thereof is administeredin an amount of about 5 mg per day.

In one preferred embodiment, the selegiline or pharmaceuticallyacceptable salt thereof is administered in an amount of from about 1 toabout 15 mg per day, more preferably, about 1.25 to about 10 mg/day.

In one preferred embodiment, the selegiline or pharmaceuticallyacceptable salt thereof is administered in an amount of about 5 to about10 mg per day. In one highly preferred embodiment, the selegiline orpharmaceutically acceptable salt thereof is administered in an amount ofabout 5 mg per day.

In one preferred embodiment, the unit dosage comprises a 5 mg tablet ofselegiline hydrochloride.

In one preferred embodiment, the selegiline or pharmaceuticallyacceptable salt thereof is administered once a day, for example, one 5mg tablet per day.

In another preferred embodiment, the selegiline or pharmaceuticallyacceptable salt thereof is administered twice a day, for example, half a5 mg tablet twice a day.

In another preferred embodiment, the selegiline or pharmaceuticallyacceptable salt thereof is administered once a day, for example, two 5mg tablets once a day. In another preferred embodiment, the selegilineor pharmaceutically acceptable salt thereof is administered twice a day,for example, one 5 mg tablet twice a day.

Advantageously, administering the selegiline, or pharmaceuticallyacceptable salt thereof, in two daily doses can lead to a reduction incertain side effects, such as transient fullness of head or headachesdue to vasodilation. Preferably, where the selegiline, orpharmaceutically acceptable salt thereof, is administered twice a day,half a tablet is taken in the morning, and half a tablet is taken atnight.

In another preferred embodiment, the selegiline or pharmaceuticallyacceptable salt thereof is administered in a total daily dose of no morethan 5 mg per day.

The present invention is further described by way of the followingnon-limiting examples and FIGURES, wherein:

FIG. 1 shows the daily dosage of betahistine-dihydrochloride (mg) withand without selegeline taken by 13 patients with Menière's disease (MD)during a monotherapy (left) and during the combined therapy with 5 mg/dselegiline to respond to the treatment defined by 1 attack per threemonths. The thick black line indicates the mean dosage of betahistineper day of the 13 patients. There was a significant reduction from 895.4to 204.0 per day (mean, p<0.001, paired t-test).

EXAMPLES

Materials and Methods

Betahistine dihydrochloride tablets were obtained from Abbott (Vasomotol24 mg tablets). Selegiline hydrochloride tablets were obtained fromHexal.

Study Design

Studies by the Applicant investigated the benefits of a high-dosagebetahistine monotherapy compared with those of a lower dosage ofbetahistine in combination with the MAO B inhibitor (MAO-B) selegilineon the frequency of acute attacks of vertigo in patients with Menière'sdisease (MD).

More specifically, studies investigated the effect of combinationtherapy in 13 subjects receiving 5 mg per day selegiline hydrochloride(either as one tablet at night, or half a tablet in the morning and halfa tablet at night), in conjunction with varying amounts of betahistinedihydrochloride per day (amounts ranging from n=3 to 36, where n is thenumber of 24 mg tablets per day). All subjects had previously receivedtreatment with betahistine dihydrochloride monotherapy (in amountsranging from n=9 to 80, where n is the number of 24 mg tablets per day),and the number of vertigo attacks per month were recorded during a threemonth period of monotherapy prior to commencement of combinationtreatment. Following combination treatment, the subjects then recordedthe number of vertigo attacks per month during the last two months ofcombination treatment.

The 13 patients in this observational study fulfilled the currentdiagnostic criteria of MD [48]. Patients with the diagnosis of otherperipheral or central vestibular disorders, such as vestibular migraine,benign paroxysmal positional vertigo, paroxysmal brainstem attacks, orfunctional dizziness, were not included. Patients suffering from knowncontraindications or hypersensitivity to betahistine, such as bronchialasthma, pheochromocytoma, or treatment with other antihistaminic drugs,ulcer of the stomach or duodendum, or severe dysfunction of liver orkidney were also not treated with betahistine. Patients with knowncontraindications (e.g., use of meperidine or other opioids, tricyclicantidepressants or non-selective MAOIs, selective serotonin re-uptakeinhibitors) or hypersensitivity to selegiline were not treated with thisagent [51].

Based on the results of the BEMED trial (showing that betahistine 48 mgtid is evidently not effective) the study initially started with adosage of 96 mg tid in all patients. During the three- to six-monthlyfollow-up examinations the daily dosages were adjusted according to thepatient's response (approach: “titration” of attacks of vertigo).Patients had been treated for at least 18 months with high dosages ofbetahistine-dihydrochloride and had 1 attacks for at least three months.

An initial dosage of 5 mg/day selegiline hydrochloride was chosen(approved dosage for Parkinson's disease is 5 to 10 mg/d). In parallelthe dosage of betahistine was reduced to about a tenth of the initialdosage. The design of the observational study was approved by the localethics committee. Follow-up examinations were after 1 month and thenevery 3 months to check the efficacy of the treatment and theside-effects and to adjust the betahistine dosage if necessary. Ideally,the objective was to achieve 1 attack per three months.

Preliminary Results

Patient characteristics were as follows: n=13, 7 females, 6 males; agerange 40 to 75 yrs; mean age 58.9 yrs. Further details are shown inTable 1.

Based on the negative results of the BEMED trial, the patients startedon a dosage of betahistine of 96 mg tid. Then the dosage was adjustedaccording to the number of attacks of vertigo per three months. Thedaily betahistine-dihydrochloride dosage eventually required to achievea treatment response (≤1 attack for three months) ranged from 216 to1920 mg (mean 895.4 mg/d, FIG. 1), i.e. 9 to 80 24-mg tablets per day(mean 37.3). This was well tolerated except for some fullness of thestomach in 4 patients which responded well to the proton-pump inhibitorpantoprazole (20 to 40 mg per day).

After informing the patients that theoretically the betahistine dosagecan be reduced when a patient also takes selegiline, the dosage wasfirst reduced to about 10% of the initial dosage for three months.Finally, after the combination with 5 mg/d selegiline, the dosage neededto achieve the same benefit for at least three months was 3 to 36 24-mgtablets (mean 8.5), i.e. 72 to 864 mg/d (mean 204.9 mg/d, p<0.001,paired t-test). One patient transiently stopped the treatment withselegiline, another one reduced the dosage to 2.5 mg per day and theattacks re-occurred after 2 to 4 weeks. Six out of 13 patients reportedtransient fullness of the head or too much blood in the head during thecombined treatment; in two of them this disappeared when switching toselegiline 2.5 mg bid.

Of the 13 subjects tested, 10 were completely free from vertigo attacksduring the last four months of combination treatment. One patientsuffered only 1 vertigo attack per month during the last two months ofcombination treatment. Two patients suffered only one attack during thelast 3 months of combination treatment. One subject also noted animprovement in tinnitus symptoms. Four subjects commented that they werevery happy with the treatment. Other side effects included slight nausea(1 subject).

In the longer term (>9 months), one patient had to increase theselegiline dosage to 5 mg twice per day because the attacks hadre-occurred (up to three attacks per month); after increasing theselegiline dosage they experienced 1 attack per month. Eleven patientsare still on selegiline treatment (5 mg per day), one is on 2.5 mgselegiline per day, one patient stopped selegiline because they werefree of attacks for more than six months.

The major finding of this observational study in 13 patients is that thecombination of a lower dosage of betahistine and the MAO inhibitorselegiline (5 mg/d) has the same benefit as very high dosages ofbetahistine (of up to 1920 mg/d). This benefit can be explained by anincrease of the blood concentrations of betahistine due to reduction ofthe normally almost complete first-pass effect (99%) of betahistine,leading to plasma concentrations of less than 0.5 ng/ml [52].

Various modifications and variations of the invention will be apparentto those skilled in the art without departing from the scope and spiritof the invention. Although the invention has been described inconnection with specific preferred embodiments, it should be understoodthat the invention as claimed should not be unduly limited to suchspecific embodiments. Indeed, various modifications of the describedmodes for carrying out the invention which are obvious to those skilledin the relevant fields are intended to be covered by the presentinvention.

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TABLE 1 Clinical characteristics and dosages Dosage of betahistineDosage of (monotherapy) required betahistine in that the patient had acombination with significant effect before 5m selegiline the combinedtreatment (n of 24-mg Patient Sex, age, diagnosis (n of 24-mg tablets)tablets) 1 Female, 74 yrs, bilateral MD 80 36 2 Female, 69 yrs, MD,right 30 3 3 Female, 73 yrs, bilateral MD 9 3 4 Male, 43 yrs, bilateralMD 36 6 5 Female, 40 yrs, MD, right 60 18 6 Male, 51 yrs, bilateral MD24 3 7 Male, 43 yrs, MD, left 30 12 8 Male, 52 yrs, MD, right 18 3 9Male, 70 yrs, MD, right 50 3 10 Male, 57 yrs, bilateral MD 40 6 11 Male,52 yrs, MD, left 30 9 12 Female, 67 yrs, MD, right 18 3 13 Female, 75yrs, MD, left 60 6 MD = Menière's Disease

1-51. (canceled)
 52. A method of treating or preventing one or moresymptoms of vertigo in a subject, said method comprising administeringto a subject an effective amount of a combination of: (i) a first activeagent, which is betahistine, or a pharmaceutically acceptable saltthereof; and (ii) a second active agent, which is isocarboxazid,nialamide, phenelzine, hydracarbazine, tranylcypromine, benmoxin,iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine,phenoxypropazine, pivalylbenhydrazine, safrazine, caroxazone,bifemelane, moclobemide, pirlindole, toloxatone, minaprine, orrasagiline, or a pharmaceutically acceptable salt of isocarboxazid,nialamide, phenelzine, hydracarbazine, tranylcypromine, benmoxin,iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine,phenoxypropazine, pivalylbenhydrazine, safrazine, caroxazone,bifemelane, moclobemide, pirlindole, toloxatone, minaprine, orrasagiline.
 53. The method according to claim 52, wherein the dosage ofthe first active agent in combination with the second active agent isreduced to about a third compared to the dosage of the first activeagent administered in the absence of the second active agent.
 54. Themethod according to claim 52, wherein the subject has been previouslytreated with the first active agent in the absence of the second activeagent.
 55. The method according to claim 54, wherein the subject hasbeen previously treated with the first active agent in the absence ofthe second active agent for a period of at least 6 months.
 56. Themethod of claim 52, wherein the amount of the first active agentadministered is at least 48 mg per day.
 57. The method of claim 52,wherein the first active agent is betahistine dihydrochloride orbetahistine mesylate.
 58. The method of claim 52, wherein the secondactive agent is rasagiline, or a pharmaceutically acceptable saltthereof.
 59. The method of claim 52, wherein the first active agent isformulated for oral administration.
 60. The method of claim 52, whereinthe second active agent is formulated for oral administration.
 61. Themethod of claim 52, wherein the first active agent is administered in anamount of from about 50 to about 900 mg per day.
 62. The method of claim52, wherein the first active agent is administered three times a day.63. The method of claim 52, wherein the first active agent isadministered in unit dosage form, wherein the unit dosage comprises a 24mg tablet of betahistine dihydrochloride.
 64. The method of claim 63,wherein administration of the first active agent is from 3 to 36 tabletsper day.
 65. The method of claim 64, wherein administration of the firstactive agent is from 3 to 12 tablets per day.
 66. The method of claim63, wherein administration of the first active agent in the absence ofthe second active agent is at least 2 tablets per day.
 67. The method ofclaim 58, wherein the second active agent is administered in an amountof from about 1 to about 15 mg per day.
 68. The method of claim 58,wherein the second active agent is administered at least once a day. 69.The method of claim 68, wherein the second active agent is administeredtwice a day.
 70. The method of claim 52, wherein the vertigo is causedby, or associated with, Meniere's disease, vestibular neuritis,labyrinthitis, or benign paroxysmal positional vertigo.
 71. The methodof claim 52, wherein the administration of the first active agent andthe second active agent occurs in a single formulation.